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Type 2 Diabetes MellitusPhase 4NCT02948777

Effects of PCSK9 Inhibition by Evolocumab on Postprandial Lipid Metabolism in Type 2 Diabetes

A Phase 4 study testing Evolocumab in people with Type 2 Diabetes Mellitus, run by Marja-Riitta Taskinen at 1 site in Finland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Postprandial lipemia is highly prevalent in type 2 diabetes subjects even with normal fasting triglyceride values. Humans are mostly in a postprandial rather than in a fasting state and therefore non-fasting triglyceride values reflect more accurately the continuous exposure of arterial wall to the substantial… Read more about this study

Who is it for?
Ages 18 to 77 years
Conditions the study is for
Type 2 Diabetes Mellitus
What is being tested?
Evolocumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
14 participants
Where
1 siteFinland
Study dates
Oct 2016to Jun 2018
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 77 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female (non-fertile or using a medically approved birth control method) overweight/obese subjects with Type 2 Diabetes Mellitus treated with lifestyle counselling and a stable metformin dose for at least three months
  • age 18-77 yrs.
  • body mass index 25-40 kg/m2
  • triglycerides between 1.5-4.5 mmol/L and low-density-lipoprotein cholesterol >1.8 but ≤4.0 mmol/L (on Atorvastatin 20 mg/day)
  • glycohemoglobin: ≤9%.
  • Each patient will attend a pre-screening visit (at week -5) where eligibility criteria will be evaluated. If the patient uses another statin than atorvastatin (20 mg) at screening visit the used statin is stopped and atorvastatin 20 mg will be initiated. If the patient is not using any statin, atorvastatin 20 mg will be initiated and the lipid values will be checked after 4 weeks when all inclusion/exclusion criteria will be assessed.

Who cannot join

  • Type 1 diabetes
  • apolipoprotein E2/2 phenotype
  • alanine transaminase / aspartate transaminase > 3× upper limit of normal
  • creatinine kinase>3× upper limit of normal
  • glomerular filtration rate <60 ml/min
  • clinically significant thyroid-stimulating hormone outside the normal range
Show all 29Show fewer
  • body mass index >40 kg/m2
  • glycohemoglobin > 9.0 %
  • fasting triglycerides > 4.5 mmol/l
  • total cholesterol > 7.0 mmol/l
  • positive urine or serum pregnancy test
  • untreated or inadequately treated hypertension defined as blood pressure >160 mmHg systolic and/or >105 mmHg diastolic, use of thiazide diuretics at a dose of ≥25 mg/day
  • subject not on a stable dose of atorvastatin (20 mg/ day before randomization)
  • lipid-lowering drugs other than statins within 3 months
  • any other diabetes medication except diet + metformin
  • history/diagnosis of diabetes nephropathy / retinopathy
  • current smoking
  • weekly alcohol use over 24 doses for men and 16 for women
  • history of myocardial infarction, acute coronary syndrome or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within the last 6 mos.
  • planned revascularization (eg coronary artery bypass grafting, percutaneous coronary intervention, carotid or peripheral revascularization procedures) within 3 months of screening
  • New York Heart Association class III/IV congestive heart failure persisting despite treatment
  • history of hemorrhagic stroke
  • hypersensitivity to (evolocumab or) any of the excipients found in the drug product
  • use of estrogen therapy
  • current use of antithrombotic or anticoagulant therapy
  • known bleeding tendency that would be an contraindication to heparin test
  • history of cancer within the past 5 years (except for adequately treated basal cell skin cancer, squamous cell skin cancer or in situ cervical cancer)
  • women of childbearing potential not protected by effective birth control method and/or not willing to be tested for pregnancy
  • patient considered by the investigator or any sub-investigator as inappropriate for this study for any reason

Trial locations and contacts

1 site in 1 country.

Finland1 site
  • Helsinki University Hospital, Biomedicum 2U

    Helsinki

Other trials in Finland

About this study

Postprandial lipemia is highly prevalent in type 2 diabetes subjects even with normal fasting triglyceride values. Humans are mostly in a postprandial rather than in a fasting state and therefore non-fasting triglyceride values reflect more accurately the continuous exposure of arterial wall to the substantial cholesterol load from remnant particles. Evolocumab lowers blood LDL-cholesterol. This study evaluates the effect of evolocumab on postprandial lipid metabolism in type 2 diabetes. All participants in this study receive evolocumab treatment.

Being tested
Evolocumab
Keywords
apolipoprotein, CVD, chylomicrons, evolocumab, kinetics
Medical subject headings
Diabetes Mellitus, Type 2, Cardiovascular Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EvolocumabDrug

    Also called Repatha

Study groups in NCT02948777
Study groupRoleWhat they receive
EvolocumabExperimentalEvolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
Receives: Drug: Evolocumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Mean ApoB Concentration Before and After Evolocumab

    Change in apolipoprotein B concentration in total plasma measured by using turbidimetric immunoassay.

    Measured: Baseline and after 12 weeks

  2. Mean TRL-C Concentration Before and After Evolocumab

    Change in TRL-cholesterol concentration in plasma samples measured by using automated direct assay (Denka Seiken, Tokyo, Japan)

    Measured: Baseline and after 12 weeks

  3. Mean Total Production of ApoB48 Before and After Evolocumab

    Change in ApoB48 total production in plasma measured by using multicompartmental modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (J Clin Invest 1979;63:1262-1273) and have been widely used over 30yrs. So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019;285:562-577). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. These figures per day are used to report the data from this study.

    Measured: Baseline and after 12 weeks

  4. Mean LDL FCR of ApoB100 Before and After Evolocumab

    Change in low-density lipoprotein fractional catabolic rate of ApoB100 in LDL from plasma samples measured by multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  5. LDL Pool Size of ApoB100 Before and After Evolocumab

    Change in low-density lipoprotein pool size of ApoB100 in LDL fraction prepared from plasma samples using density ultracentrifugation.

    Measured: Baseline and after 12 weeks

Secondary outcomes (20)
  1. Mean LDL-C Concentration Before and After Evolocumab

    Change in LDL-cholesterol concentration in plasma LDL fraction isolated by ultracentrifugation.

    Measured: Baseline and after 12 weeks

  2. Mean ApoB48 Concentration Before and After Evolocumab

    Change in apolipoprotein B48 levels in total plasma measured by enzyme-linked immunosorbent assay.

    Measured: Baseline and after 12 weeks

  3. Mean CM TG-iAUC Before and After Evolocumab

    Change in chylomicron triglyceride incremental area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

    Measured: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

  4. Mean ApoB48 AUC Before and After Evolocumab

    Change in apolipoprotein B48 area under curve in plasma samples taken at particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

    Measured: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

  5. Mean VLDL1 ApoB100 Production Before and After Evolocumab

    Change in VLDL1 ApoB100 production rates measured from isolated VLDL from plasma samples using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  6. Mean VLDL2 ApoB100 Production Before and After Evolocumab

    Change in VLDL2 apoB100 production rates measured from isolated VLDL2 from plasma samples by using density ultracentrifugation and the enrichment of tracer was measured in isolated fractions following using mathematical modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  7. IDL Pool Size of ApoB100 Before and After Evolocumab

    Change in intermediate-density lipoprotein pool size of ApoB100 in IDL fraction prepared from plasma samples using density ultracentrifugation.

    Measured: Baseline and after 12 weeks

  8. Mean IDL to LDL Transfer of ApoB100 Before and After Evolocumab

    Change in ApoB100 intermediate-density lipoprotein to low-density lipoprotein transfer in isolated samples from plasma by ultracentrifugation and measured using multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  9. Mean VAT Before and After Evolocumab

    Change in visceral fat volume measured by magnetic resonance imaging

    Measured: Baseline and after 12 weeks

  10. Mean Liver Fat Before and After Evolocumab

    Change in liver fat content measured by magnetic resonance imaging.

    Measured: Baseline and after 12 weeks

  11. Mean SAT Before and After Evolocumab

    Change in subcutaneous fat volume measured by magnetic resonance imaging

    Measured: Baseline and after 12 weeks

  12. Mean VLDL1 Triglyceride Production Before and After Evolocumab

    Change in VLDL1 triglyceride production measured from isolated VLDL1 from plasma samples by using density gradient ultracentrifugation. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  13. Mean VLDL1 FCR of triglycerideBefore and After Evolocumab

    Change in VLDL1 fractional catabolic rate of triglyceride measured in isolated VLDL1 from plasma samples by using density ultracentrifugation and measured by multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  14. Mean VLDL2 Triglyceride Total Production Before and After Evolocumab

    Change in VLDL2 triglyceride total production measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and measured by multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  15. Mean VLDL2 FCR of Triglyceride Before and After Evolocumab

    Change in VLDL2 fractional catabolic rate of triglyceride measured in isolated VLDL2 from plasma samples by using density ultracentrifugation and measured by multicompartmental modeling. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  16. Mean Postprandial CM of ApoB48 Before and After Evolocumab

    Change in Postprandial chylomicron of ApoB48 measured from plasma samples by liquid chromatography-mass spectrometry with multicompartmental modeling assay. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  17. Mean CM-apoB48 FCR of ApoB48 Metabolism Before and After Evolocumab

    Change in chylomicron-apoB48 fractional catabolic rate of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  18. Mean CM-TG Production of ApoB48 Before and After Evolocumab

    Change in chylomicron-triglycerides production of ApoB48 in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. Production rates were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90, 120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. More detailed description see Outcome measure 3.

    Measured: Baseline and after 12 weeks

  19. Mean CM TG-AUC Before and After Evolocumab

    Change in chylomicron triglyceride area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

    Measured: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

  20. Mean ApoB48 iAUC Before and After Evolocumab

    Change in apolipoprotein B48 incremental area under curve in plasma at a particular time points after the meal. Area under the curve (AUC) was normalized so that 100% corresponds to the AUC before treatment; subsequently the percentage after treatment is in reference to this value. AUC values were calculated using the trapezoidal rule.

    Measured: 0, 2, 4, 6, 8 hours after the meal at baseline and after 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Oct 2016 (estimated)
  2. Study startOct 2016
  3. Primary completionJun 2018
  4. Study completionJun 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02948777
Sponsor's protocol ID
EVOLKIN
Status last verified
Oct 2021
First submitted
27 Oct 2016
Last updated
3 Nov 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Taskinen MR, Bjornson E, Kahri J, Soderlund S, Matikainen N, Porthan K, Ainola M, Hakkarainen A, Lundbom N, Fermanelli V, Fuchs J, Thorsell A, Kronenberg F, Andersson L, Adiels M, Packard CJ, Boren J. Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes. Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):962-975. doi: 10.1161/ATVBAHA.120.315446. Epub 2020 Dec 24.

    PubMed 33356392
  • Taskinen MR, Bjornson E, Andersson L, Kahri J, Porthan K, Matikainen N, Soderlund S, Pietilainen K, Hakkarainen A, Lundbom N, Nilsson R, Stahlman M, Adiels M, Parini P, Packard C, Boren J. Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects. J Clin Lipidol. 2020 Jan-Feb;14(1):77-87. doi: 10.1016/j.jacl.2019.12.003. Epub 2019 Dec 12.

    PubMed 31917184
  • Zech LA, Grundy SM, Steinberg D, Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects. J Clin Invest. 1979 Jun;63(6):1262-73. doi: 10.1172/JCI109421.

    PubMed 221537
  • Bjornson E, Packard CJ, Adiels M, Andersson L, Matikainen N, Soderlund S, Kahri J, Sihlbom C, Thorsell A, Zhou H, Taskinen MR, Boren J. Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics. J Intern Med. 2019 May;285(5):562-577. doi: 10.1111/joim.12877. Epub 2019 Mar 12.

    PubMed 30779243
  • Taskinen MR, Matikainen N, Bjornson E, Soderlund S, Inkeri J, Hakkarainen A, Parviainen H, Sihlbom C, Thorsell A, Andersson L, Adiels M, Packard CJ, Boren J. Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy. Diabetologia. 2023 Dec;66(12):2307-2319. doi: 10.1007/s00125-023-06008-0. Epub 2023 Sep 29.

    PubMed 37775612

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Evolocumab in people with Type 2 Diabetes Mellitus, run by Marja-Riitta Taskinen at 1 site in Finland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean ApoB Concentration Before and After Evolocumab (time frame: Baseline and after 12 weeks). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02948777, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2021.

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